Trifluoroacetic acid → (R)-N-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-2-yl)quinolin-7-amine 2,2,2-trifluoroacetate

HRID 1812303Notes

Reaction equation

HRID 1812303 reaction equation
COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:34][C:35]4[CH:44]=[C:43]5[C:38]([CH:39]=[CH:40][CH:41]=[N:42]5)=[CH:37][CH:36]=4)=[N:18][CH:19]=[C:20]([C@H:22]([N:24]4[CH2:29][CH2:28][N:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:26][CH2:25]4)[CH3:23])[CH:21]=3)[N:10]=2)=CC=1.FC(F)(F)S(O)(=O)=O.[C:64]([OH:70])([C:66]([F:69])([F:68])[F:67])=[O:65]>>[F:67][C:66]([F:69])([F:68])[C:64]([OH:70])=[O:65].[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[C:17]([NH:34][C:35]3[CH:44]=[C:43]4[C:38]([CH:39]=[CH:40][CH:41]=[N:42]4)=[CH:37][CH:36]=3)=[N:18][CH:19]=[C:20]([C@H:22]([N:24]3[CH2:25][CH2:26][N:27]([S:30]([CH3:33])(=[O:31])=[O:32])[CH2:28][CH2:29]3)[CH3:23])[CH:21]=2)[N:10]=1

Participants

4

Reactant 3

HCID 6422Trifluoroacetic acidHCID 62406Trifluoromethanesulfonic acidHCID 66611507HCID 66611507, compound

Product 1

HCID 66611404(R)-N-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-2-yl)quinolin-7-amine 2,2,2-trifluoroacetateYield 36.5%

Conditions

Temperature
25 °C

Procedure

A brown solution of (R)-N-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-2-yl)quinolin-7-amine (170.8 mg, 0.225 mmol) and trifluoromethanesulfonic acid (0.2 mL, 2.252 mmol) (10% v/v with TFA) in TFA (2.0 mL) was stirred at 75° C. for 1.5 h. The reaction mixture was subsequently cooled to 25° C. and concentrated in vacuo. The residue was taken up in CH2Cl2 (50 mL), and the resulting solution was washed with saturated aqueous sodium bicarbonate (40 mL). The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (2×30 mL). All organic layers were then combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was taken up in DMSO (2.0 mL) and purified by rpHPLC (Phenomenex Luna 5 μm C18, 30×150 mm, 45 mL/min, 10 to 100% CH3CN/H2O (plus 0.1% TFA, both solvents)) to provide (R)-N-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-2-yl)quinolin-7-amine 2,2,2-trifluoroacetate (52.0 mg, 0.082 mmol, 36.5% yield) as a yellow-orange solid. 1H NMR (400 MHz, d4-MeOH) δ 9.52 (d, J=1.8 Hz, 1H), 9.18 (d, J=2.5 Hz, 1H), 8.99 (d, J=8.2 Hz, 1H), 8.96 (dd, J=5.6, 1.3 Hz, 1H), 8.68 (d, J=2.5 Hz, 1H), 8.25 (d, J=9.2 Hz, 1H), 8.04 (dd, J=9.0, 2.0 Hz, 1H), 7.83 (dd, J=8.0, 5.7 Hz, 1H), 4.70 (q, J=7.0 Hz, 1H), 3.55 (br. s., 4H), 2.94 (s, 3H), 2.65 (s, 4H), 2.58 (s, 3H), 1.89 (d, J=6.8 Hz, 3H). 19F NMR (376 MHz, d4-MeOH) δ −77.36 (s, 3F). m/z (ESI, +ve) 520.2 (M+H)+.

Workup

  1. concentrationconcentrated in vacuo
  2. washthe resulting solution was washed with saturated aqueous sodium bicarbonate (40 mL)
  3. customThe organic layer was separated
  4. extractionthe aqueous layer was extracted with CH2Cl2 (2×30 mL)
  5. dry with materialdried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. custompurified by rpHPLC (Phenomenex Luna 5 μm C18, 30×150 mm, 45 mL/min, 10 to 100% CH3CN/H2O (plus 0.1% TFA

Sources & evidence

ORD record
ord-c42cdf88e63649b7b5baa423ddd9b6e6
Source dataset
uspto-grants-2013_01
Patent number
US08362241B2

Reaction notes

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